Phenobarbital (PB) antagonizes and SKF 525A potentiates delta-9- tetrahydrocannabinol (THC)-induced mortality. PB is a prototype drug which increases the metabolic system capable of biotransforming THC. Many other drugs possess the same ability to stimulate the biotransforming system. SKF 525A is a prototype drug which inhibits the biotransforming system. Again, many other drugs are capable of inhibiting the biotransformation system when administered concommitantly. Both PB and SKF 525A alter THC plasma concentrations, distribution, and excretion. SKF 525A pretreatment resulted in significantly higher plasma and brain THC levels. Male mice are more sensitive to THC-induced toxicity than female mice. Presence of liver injury produced a 3- to 5-fold increase in THC-induced lethality when compared to THC alone. The vehicle in which THC was administered influenced THC-induced toxicity. THC suspended in Tween 80 and saline is five times more toxic than the same dosage administered in an oil solution. THC is fetocidal and fetopathic when administered to pregnant mice. THC produced a significant incidence of in utero deaths, reduction of body size and offspring with cleft palate. These effects were related to both dosage and day administration. THC, 50 milligrams/kg, administered during early organogenesis produced 49% resorptions, while the same dosage administered during late organogenesis produced no significant increase in fetal resorptions. THC administered to pregnant mice significantly reduced the body weight of surviving fetuses. Examination of skeletal development showed no anomalies. THC was transferred across the placenta and was measured in fetal tissue and amnionic fluid. THC-induced teratogenesis can be modified by PB and SKF 525A pretreatment. SKF 525A treatment significantly increases the incidence of THC-induced in utero fetal deaths. THC at 50 milligrams/kg produced 9% fetal resorptions, while the same treatment after SKF 525A produced 66% fetal resorptions. PB pretreatment antagonizes and SKF 525A pretreatment potentiates the effect of THC on cleft palate induction. These data suggest that factors which alter THC metabolism also influence THC-induced teratogenesis.